The major objectives of this research proposal are: 1) to study mechanisms that control erythropoietin (Ep) production and erythropoiesis in the mammalian fetus, 2) to investigate factors that favor hepatic rather than renal Ep formation, 3) to evaluate the kinetics (delay or acceleration) of the liver-kidney switch of Ep formation, and 4) to assess the in vivo effects of various agents and conditions on the type (fetal or adult) and relative concentration of hemoglobin in different hematopoietic organs during fetal growth and development. These studies will be performed in fetal, newborn and adult sheep before and after treatment with androgens and thyroid hormones; following induction of chronic anemia and polycythemia, chronic partial hepatectomy and/or bilateral nephrectomy, and thyroid gland ablation. In addition, the influence of maternal hypoxia on erythropoiesis in normal and polycythemic fetuses will be investigated. The influence on erythropoiesis and hemoglobin production will be assessed using both in vitro and in vivo procedures, and will include the study of the effect of the different experimental conditions listed above the organ-distribution of erythroid progenitors. These studies will lead to a better understanding of the processes involved in the regulation of red cell production in the fetus, provide information regarding agents or conditions effective in the activation of the extra-renal site of Ep formation in the adult, and provide a useful index of the degree of hypoxia to which the fetus may be exposed in certain clinical and experimental conditions.